Liquid, and especially concentrated liquid pharmaceutical compositions offer several advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Moreover, liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Likewise, concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of this nature permits the accurate and uniform delivery of unit dose amounts of a pharmaceutical active, encompassing even those instances where relatively small amounts of a pharmaceutical active are to be delivered. In addition, soft gelatin capsules are aesthetically appealing (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
These advantages notwithstanding, it is, however, often difficult to prepare such compositions using the desired pharmaceutical active. Many pharmaceutical actives are poorly soluble and, therefore, require relatively large volumes of solvent for dissolution, resulting in impractically large doses. Also, encapsulating such large volumes into easy-to-swallow gelatin capsules presents obvious difficulties, suggesting the immediate importance of concentrated liquid compositions. Furthermore, the situation becomes even more complicated when multiple pharmaceutical actives are involved, and particularly where the difficultly soluble pharmaceutical active is in combination with a water soluble pharmaceutical active(s).
The current approach to this solubility problem is to force solubility into small volumes of solvent by means of a step-wise process incorporating intense heat. This step-wise process consists of dissolving the difficultly soluble pharmaceutical active in polyethylene glycol with heat, followed by the addition of any additional pharmaceutical actives. As a separate admixture, polyvinylpyrrolidone is dissolved in a solution of water and propylene glycol. Finally, the polyvinylpyrrolidone solution is then added to the original batch solution to complete the process. While this process has proved to be quite useful in enhancing the solubility of difficultly soluble pharmaceutical actives, there is still a need to improve the stability of the resultant liquid composition. Because the resultant concentrated liquid (or fill) is a supersaturated solution of the difficultly soluble pharmaceutical active, there is a tendency for the dissolved difficultly soluble active to precipitate out of solution.
The present inventor has unexpectantly discovered that by simply changing the order in which certain components are added under the current process, a new composition results having improved stability.
It is, therefore, an object of the present invention to describe a process which provides decreased precipitation of the difficultly soluble pharmaceutical active(s), thus improving the resultant composition's stability. These and other objects of this invention will become apparent in light of the following discussion.